title: TNF-α and its receptors modulate complex behaviours and neurotrophins in transgenic mice.
abstract: Tumour necrosis factor-α (TNF-α) plays an important role not only in immunity but also in the normal functioning of the central nervous system (CNS). At physiological levels, studies have shown TNF-α is essential to maintain synaptic scaling and thus influence learning and memory formation while also playing a role in modulating pathological states of anxiety and depression. TNF-α signals mainly through its two receptors, TNF-R1 and TNF-R2, however the exact role that these receptors play in TNF-α mediated behavioural phenotypes is yet to be determined.
  
  
  METHODS
  We have assessed TNF(-/-), TNF-R1(-/-) and TNF-R2(-/-) mice against C57BL/6 wild-type (WT) mice from 12 weeks of age in order to evaluate measures of spatial memory and learning in the Barnes maze (BM) and Y-maze, as well as other behaviours such as exploration, social interaction, anxiety and depression-like behaviour in a battery of tests. We have also measured hippocampal and prefrontal cortex levels of the neurotrophins nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) as well as used immunohistochemical analyses to measure number of proliferating cells (Ki67) and immature neurons (DCX) within the dentate gyrus.
  
  
  RESULTS
  We have shown that young adult TNF(-/-) and TNF-R1(-/-) mice displayed impairments in learning and memory in the BM and Y-maze, while TNF-R2(-/-) mice showed good memory but slow learning in these tests. TNF(-/-)and TNF-R2(-/-) mice also demonstrated a decrease in anxiety like behaviour compared to WT mice. ELISA analyses showed TNF(-/-) and TNF-R2(-/-) mice had lower levels of NGF compared to WT mice.
  
  
  CONCLUSIONS
  These results indicate that while lack of TNF-α can decrease anxiety-like behaviour in mice, certain basal levels of TNF-α are required for the development of normal cognition. Furthermore our results suggest that both TNF-R1 and TNF-R2 signalling play a role in normal CNS function, with knockout of either receptor impairing cognition on the Barnes maze.
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia; Discipline of Anatomy, School of Medicine, James Cook University, Townsville, QLD, Australia.
authors.forename: Marie Lou
authors.initials: ML
authors.lastname: Camara
authors.forename: Frances
authors.initials: F
authors.lastname: Corrigan
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Jaehne
authors.forename: M Catharine
authors.initials: MC
authors.lastname: Jawahar
authors.forename: Helen
authors.initials: H
authors.lastname: Anscomb
authors.forename: Heinrich
authors.initials: H
authors.lastname: Koerner
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology*; D003863:Depression / Q000523:psychology; D000089662:Doublecortin Protein; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D007398:Interpersonal Relations; D007858:Learning / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009414:Nerve Growth Factors / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D009414:Nerve Growth Factors; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: Anxiety; Cognition; Depression; Neurogenesis; Neurotrophins; Sociability; TNF-R1; TNF-R2; TNF-α